Solid forms of an alpha, omega di-substituted dihydroxy cyclopentyl compound and methods for the preparation and use thereof

ABSTRACT

Provided herein are multiple solid forms of a defined α,{acute over (ω)}-disubstituted dihydroxy cyclopentyl compound, and methods for the preparation and use thereof. In one aspect, there are provided crystalline forms of said cyclopentyl compound, and methods for the preparation and use thereof. In another aspect, there are provided substantially amorphous forms of said dihydroxy cyclopentyl compound, and methods for the preparation and use thereof. In yet another aspect, there are provided compositions containing compounds according to the present invention. In certain aspects, such compositions are suitable for delivery of active agents according to the present invention to a subject in need thereof. In another aspect of the invention, there are provided methods for the treatment of a variety of indications, including glaucoma, ocular hypertension, and the like. In still another aspect of the present invention, there are provided kits containing compounds according to the present invention and/or compositions containing same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. patent application Ser. No.14/569,210, filed Dec. 12, 2014, which in turn claims the benefit ofU.S. provisional application 61/915,575 (docket number 19333PROV (AP))entitled “Solid Forms Of An Alpha, Omega Di-Substituted DihydroxyCyclopentenyl Compound And Methods For The Preparation And Use Thereof”filed on Dec. 13, 2013, the disclosures of which are hereby incorporatedby reference in their entireties and serve as the basis of a priorityand/or benefit claim for the present application.

FIELD OF THE INVENTION

The present invention relates to solid forms of an α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compound, and methods for thepreparation and use thereof. In one aspect, the present inventionrelates to crystalline forms of an α,{acute over (ω)}-disubstituteddihydroxy cyclopentyl compound, and methods for the preparation and usethereof. In another aspect, the present invention relates tosubstantially amorphous forms of an α,{acute over (ω)}-disubstituteddihydroxy cyclopentyl compound, and methods for the preparation and usethereof.

BACKGROUND OF THE INVENTION

The α,{acute over (ω)}-disubstituted dihydroxy cyclopentyl compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide:

is a potent ocular hypotensive particularly suited for, inter alia, themanagement of glaucoma (see, e.g., U.S. Pat. No. 6,602,900).

Many drug compounds exist in one or more crystalline forms, referred toas polymorphs. These polymorphs of the same molecule exhibit differentphysical properties, such as melting point, solubility, hardness, etc.In such cases, the danger exists of less soluble polymorphic formsprecipitating from a solution made from another more soluble but lessstable form. For example, the formation of crystals in an ophthalmicsolution can cause serious injury to the eye. In addition, precipitationof the drug substance may cause an apparent reduction in potency andbioavailability of the product.

Accordingly, there is need for novel crystalline forms of compounds suchas the α,{acute over (ω)}-disubstituted dihydroxy cyclopentyl compounddescribed herein.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided multiplesolid forms of an α,{acute over (ω)}-disubstituted dihydroxy cyclopentylcompound, and methods for the preparation and use thereof. In oneaspect, there are provided crystalline forms of an α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compound, and methods for thepreparation and use thereof. In another aspect, there are providedsubstantially amorphous forms of an α,{acute over (ω)}-disubstituteddihydroxy cyclopentyl compound, and methods for the preparation and usethereof.

In accordance with yet another aspect of the present invention, thereare provided compositions containing said α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compound. In certain aspects,such compositions are suitable for delivery of said α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compound to a subject in needthereof. In certain aspects, the invention relates to methods for thetreatment of a variety of indications, including glaucoma, ocularhypertension, and the like.

In accordance with a further aspect of the present invention, there areprovided kits containing said α,{acute over (ω)}-disubstituted dihydroxycyclopentyl compound and/or compositions containing same.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1C present exemplary X-ray powder diffraction (XRPD)patterns for crystalline Form A of the α,{acute over (ω)}-disubstituteddihydroxy cyclopentyl compound described herein. Major peaks unique toForm A include peaks at about 12.01, 14.09, 20.14, 20.47 and 23.72degrees 2θ. FIGS. 1B and 1D present exemplary X-ray powder diffraction(XRPD) patterns for crystalline Forms B of the α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compound described herein.Major peaks unique to Form B include peaks at about 11.64, 19.57, 21.99,22.74 and 25.06 degrees 2θ.

FIG. 2 presents thermogravimetric analysis/differential scanningcalorimetry (TGA/DSC) curves for crystalline solid Form A of theα,{acute over (ω)}-disubstituted dihydroxy cyclopentyl compounddescribed herein. Melting of Form A starts at about 37° C., and ends atabout 65° C. An endothermic peak at 254° C. is attributed todecomposition of the compound.

FIG. 3 presents TGA/DSC curves for crystalline solid Form B of theα,{acute over (ω)}-disubstituted dihydroxy cyclopentyl compounddescribed herein. Melting of Form B starts at about 25° C., and ends atabout 60° C. An endothermic peak at 254° C. is attributed todecomposition of the compound.

FIG. 4A presents an XRPD pattern of a sample of crystalline Form A afterbeing maintained at 22±2° C. and relative humidity of 0% for 144 hours.FIG. 4B presents an XRPD pattern of a sample of crystalline Form A afterbeing maintained at 40° C. for 25 minutes.

FIG. 5 presents an XRPD pattern of a sample of crystalline Form A afterbeing maintained at 22±2° C. and relative humidity of 59% for 144 hours.

FIG. 6A presents an XRPD pattern of a sample of crystalline Form B afterbeing maintained at 22±2° C. and relative humidity of 59% for 120 hours.FIG. 6B presents an XRPD pattern of a sample of crystalline Form B afterbeing maintained at 40° C. for 25 minutes.

FIG. 7 presents an XRPD pattern of a sample of crystalline Form B afterbeing maintained at 22±2° C. and relative humidity of 0% for 120 hours.

FIG. 8 presents an XRPD pattern of a sample of crystalline Form B afterbeing maintained 40° C. for 16 hours.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided solid formsof the α,{acute over (ω)}-di substituted dihydroxy cyclopentyl compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide,i.e., the compound having the structure:

In certain embodiments of the invention, the solid form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamideis a crystalline anhydrate (Form A). Such crystalline forms can befurther characterized by the X-ray powder diffraction (XRPD) patternthereof. An exemplary XRPD pattern for crystalline Form A of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide has at least thefollowing peaks at about 12.01, 14.09, 20.14, 20.47 and 23.72 degrees2θ.

exemplary XRPD patterns for crystalline Form A of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide aresubstantially as shown in FIGS. 1A and 1C. A skilled person wouldrealize that, in general, the position of the 2θ peaks in an XRPDpattern can vary by approximately 0.1, and thus exemplary peaks of thecrystal form herein described would appear at about 12.01, 14.09, 20.14,20.47 and 23.72 degrees 2θ, wherein the term “about” indicates peaks at12.0±0.1, 14.1±0.1, 20.1±0.1, 20.5±0.1 and 23.7±0.1 degrees 2θ in anXRPD pattern. A skilled person would also understand that similarvariations would apply to the other 2θ peaks in FIGS. 1A and 1C whichcan also vary by approximately 0.1.

In some embodiments of the present invention, crystalline Form A of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide has a meltingendotherm at about 62° C. and a decomposition endotherm at about 254° C.

Crystalline Form A can be further characterized as remainingsubstantially unchanged when maintained at a temperature in the range ofabout 25-40° C. under dry conditions, whereas a substantial portionthereof converts to Form B when maintained at ambient temperature and arelative humidity of about 59% for at least 72 hours. As used herein,“substantially unchanged” means that the indicia that a sample exists incrystalline Form A (e.g., the presence of the unique XRPD peaks referredto herein) remain clearly discernible. As used herein, “substantialportion thereof” refers to the major portion of the sample in question,i.e., greater than 50% of the sample, undergoes conversion from Form Ato Form B; in some embodiments, greater than 60% of the sample undergoesconversion from Form A to Form B; in some embodiments, greater than 70%of the sample undergoes conversion from Form A to Form B; in someembodiments, greater than 80% of the sample undergoes conversion fromForm A to Form B; in some embodiments, greater than 90% of the sampleundergoes conversion from Form A to Form B.

Crystalline Form A can also be characterized with reference to thedifferential scanning calorimetry (DSC) profile thereof; an exemplaryDSC profile thereof is as shown in FIG. 2.

In some embodiments of the present invention, crystalline Form A issubstantially free of other solid forms. As used herein, “substantiallyfree” refers to samples wherein the presence of alternate solid formsfalls below the detection limit, i.e., less than about 10% of said solidis in a form other than crystalline Form A.

In addition, the crystalline Form A described herein has a differentialscanning calorimetry profile as shown in FIG. 2, showing melting of FormA starting at about 37° C., and ending at about 65° C., with anendothermic peak at 254° C. attributed to decomposition of the compound.This profile shows a single melting event indicating that Form A isessentially a pure crystal and does not contain any other crystallineforms. Accordingly, a skilled person would understand that thecrystalline Form A described herein can be substantially free of othercrystalline forms based on its DSC profile.

In certain embodiments of the present invention, the solid form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamideis a crystalline hydrate (Form B). In some embodiments, the crystallinehydrate is a hemihydrate.

An exemplary XRPD pattern for crystalline Form B of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide is substantiallyas shown in FIGS. 1B and 1D has peaks at least at about 11.64, 19.57,21.99, 22.74 and 25.06 degrees 2θ.

Exemplary XRPD pattern for crystalline Form B of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide aresubstantially as shown in FIGS. 1B and 1D. A skilled person wouldrealize that, in general, the position of the 2θ peaks in an XRPDpattern can vary by approximately 0.1, and thus exemplary peaks of thecrystal form herein described would appear at about (2θ) 11.64, 19.57,21.99, 22.74 and 25.06, wherein the term “about” indicates peaks at (2θ)11.6±0.1, 19.6±0.1, 22.0±0.1, 22.7±0.1 and 25.1±0.1 in an XRPD pattern.A skilled person would also understand that similar variations wouldapply to the other 2θ peaks in FIGS. 1B and 1D which can also vary byapproximately 0.1.

In some embodiments of the present invention, crystalline Form B of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide has a meltingendotherm at about 50° C. and a decomposition endotherm at about 254° C.

Crystalline Form B can be further characterized as remainingsubstantially unchanged when maintained for up to about 1 hour at arelative humidity of about 59% and ambient temperature, or at atemperature of about 40° C. or under dry conditions, whereas asubstantial portion thereof converts to amorphous form when maintainedat a temperature of at least about 40° C. for at least 12 hours. As usedherein, “substantially unchanged” means that the indicia that a sampleexists in crystalline Form B (e.g., the presence of the unique XRPDpeaks referred to herein) remain clearly discernible. As used herein,“substantial portion thereof” refers to the major portion of the samplein question, i.e., greater than 50% of the sample, undergoes conversionfrom Form B to the amorphous form; in some embodiments, greater than 60%of the sample undergoes conversion from Form B to the amorphous form; insome embodiments, greater than 70% of the sample undergoes conversionfrom Form B to the amorphous form; in some embodiments, greater than 80%of the sample undergoes conversion from Form B to the amorphous form; insome embodiments, greater than 90% of the sample undergoes conversionfrom Form B to the amorphous form.

Crystalline Form B can also be characterized with reference to the DSCprofile thereof; an exemplary DSC profile thereof is as shown in FIG. 3.

In some embodiments of the present invention, crystalline Form B issubstantially free of other solid forms. As used herein, “substantiallyfree” refers to samples wherein the presence of alternate solid formsfalls below the detection limit, i.e., less than about 10% of said solidis in a form other than crystalline Form B.

In addition, the crystalline Form B described herein has a differentialscanning calorimetry profile as shown in FIG. 3, showing melting of FormB starting at about 25° C., and ending at about 60° C., with anendothermic peak at 254° C. attributed to decomposition of the compound.This profile shows a single melting event indicating that Form B isessentially a pure crystal and does not contain any other crystallineforms. Accordingly, a skilled person would understand that thecrystalline Form B described herein can be substantially free of othercrystalline forms based on its DSC profile.

In certain embodiments of the invention, the solid form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamideis substantially amorphous. As used herein, “substantially amorphous”refers to samples wherein the majority of the active compound thereinhas no indicia of crystal structure, e.g., wherein XRPD analysis revealsno discernible peaks in an XRPD evaluation thereof.

In accordance with another embodiment of the present invention, thereare provided pharmaceutical compositions comprising a therapeuticallyeffective amount of:

-   crystalline Form A of 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-di    chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide,-   crystalline Form B of 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-di    chloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide,-   a substantially amorphous form of    7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide,    or-   combinations of any two or more thereof,    in an ophthalmically acceptable carrier therefore.

Those skilled in the art can readily identify ophthalmically acceptablecarriers suitable for administration (or the manufacture of medicamentscontaining) the α,{acute over (ω)}-disubstituted dihydroxy cyclopentylcompounds disclosed herein. Specifically, a drug to be administeredsystemically may be confected as a solution, emulsion, suspension,aerosol, or the like.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsaccording to the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuricacetate, phenylmercuric nitrate, and the like. A useful surfactant is,for example, Tween 80. Likewise, various useful vehicles may be used inthe ophthalmic preparations according to the present invention. Thesevehicles include, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose, purified water, and the like.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersincluding acetate buffers, citrate buffers, phosphate buffers, boratebuffers, and the like, are contemplated for use herein. Acids or basesmay be used to adjust the pH of these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inaccordance with the present invention includes, but is not limited to,sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole, butylated hydroxytoluene, and the like.

Other excipient components which may be included in the ophthalmicpreparations contemplated herein are chelating agents. A usefulchelating agent is edetate disodium, although other chelating agents mayalso be used in place of, or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjuster 1-10 buffer 0.01-10   pH adjusterq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

The amount of the α,{acute over (ω)}-disubstituted dihydroxy cyclopentylcompound administered is dependent on the therapeutic effect or effectsdesired, on the specific mammal being treated, on the severity andnature of the mammal's condition, on the manner of administration, onthe potency and pharmacodynamics of the particular compound or compoundsemployed, and on the judgment of the prescribing physician.Therapeutically effective dosages contemplated for α,{acute over(ω)}-disubstituted dihydroxy cyclopentyl compounds according to thepresent invention may be in the range of about 0.5 or about 1 to about100 mg/kg/day.

In one embodiment of the present invention, compositions describedherein are packaged in a dropper for ophthalmic application.

Compounds according to the present invention are useful for thetreatment of a variety of indications, e.g., inflammatory eye conditions(e.g., dry eye disease, conjunctivitis, and the like), glaucoma, and thelike.

In accordance with one aspect of the present invention, use of compoundsaccording to the invention in the treatment and/or prevention, and/or inthe manufacture of a medicament for the treatment and/or prevention, ofany of the above-referenced diseases and/or conditions is alsocontemplated.

Therefore, in accordance with yet another embodiment of the presentinvention, there are provided methods for reducing ocular hypertensioncomprising administering to a subject in need thereof a therapeuticallyeffective amount of a composition as described herein.

In accordance with still another embodiment of the present invention,there are provided methods for treating glaucoma comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a composition as described herein.

In one embodiment of the above-referenced methods, the compositionsaccording to the present invention are administered via topicaladministration to an eye.

“Treatment,” “treat,” or any other form of these words as used hereinare intended to mean use in the diagnosis, cure, mitigation, treatment,or prevention of disease in man or other animals.

In accordance with yet another embodiment of the present invention,there are provided methods for preparing defined solid forms of thecompound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamideemploying one or more of the following crystallization techniques, e.g.,evaporation, cooling, slurry, vapor diffusion, and the like.

In accordance with a further embodiment of the present invention, thereare provided methods for preparing Form A of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide from theamorphous state thereof, said method comprising:

(a) suspending and/or dissolving said compound in a suitable diluent,

(b) subjecting the resulting suspension and/or solution to:

-   -   (i) conditions suitable for evaporation of diluent therefrom,        and thereafter triturating the resulting oil with a suitable        non-polar solvent,    -   (ii) gradually reducing the temperature thereof, and    -   (iii)(a) storing a suspension thereof at room temperature for a        time sufficient for crystals of said compound to form, or (b)        gradually adding sufficient non-solvent thereto to promote        precipitation of said compound therefrom.

As used herein, “suitable diluent” refers to media in which the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide can be suspendedand/or dissolved. Exemplary diluents include ketones (e.g., acetone,methyl ethyl ketone, and the like), alcohols (e.g., methanol, ethanol,propanol, butanol, and the like), esters (e.g., ethyl acetate), nitriles(e.g., acetonitrile), ethers (e.g., diethyl ether, methyl tert-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and the like),alkanes (e.g., hexane, heptane, and the like), chlorinated hydrocarbons(e.g., dichloromethane, chloroform, and the like), aromatics (e.g.,benzene, toluene, and the like), as well as mixtures of any two or morethereof.

As used herein, “conditions suitable for evaporation of diluenttherefrom” refers to the combination of temperature and/or atmospherethat promotes removal of diluent from a suspension or solution. Forexample, elevated temperatures at atmospheric pressure can be employed;alternatively, ambient temperature can be employed at reduced pressures;or the combination of elevated temperature and reduced pressure can beemployed to promote evaporation of diluent from a suspension or solutioncontaining an α,{acute over (ω)}-disubstituted dihydroxy cyclopentylcompound according to the present invention.

As used herein, “suitable non-polar solvent” refers to a solvent ofsufficiently low polarity to induce crystal formation of a polarcompound such as the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide, e.g., an ether.

As used herein, “time sufficient for crystals . . . to form” refers tothe amount of time required for a given sample to equilibrate into thesolid form preferred under the particular conditions. The amount of timerequired to do so can vary from minutes to days; typically 1-14 days isadequate for such purpose.

As used herein, “non-solvent” refers to medium in which the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide is notappreciably soluble; therefore, the use of “sufficient” non-solventcontemplates the addition of a quantity of non-solvent sufficient toinduce precipitation and/or crystallization of the majority of saidcompound from a solution or suspension containing same.

In accordance with a further embodiment of the present invention, thereare provided methods for preparing Form B of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide from theamorphous state, said method comprising:

(a) suspending and/or dissolving said compound in a suitable diluent,

(b) subjecting the resulting suspension and/or solution to:

-   -   (i) conditions suitable for evaporation of diluent therefrom,        and thereafter triturating the resulting oil with a suitable        polar solvent,    -   (ii) gradually reducing the temperature thereof, and    -   (iii)(a) storing a suspension thereof at room temperature for a        time sufficient for crystals of said compound to form, or (b)        gradually adding sufficient non-solvent thereto to promote        precipitation of said compound therefrom.

In accordance with a further embodiment of the present invention, thereare provided methods for converting Form A of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide into Form Bthereof, said method comprising subjecting Form A of said compound to arelative humidity of about 59% at ambient temperature for at least 72hours.

In accordance with another aspect of the present invention, there areprovided kits comprising the compositions described herein, a container,and instructions for administration of said composition to a subject inneed thereof for the mitigation of glaucoma, ocular hypertension, or thelike.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs is contemplated:

-   -   β-Blockers (or β-adrenergic antagonists) including carteolol,        levobunolol, metiparanolol, timolol hemihydrate, timolol        maleate, β1-selective antagonists such as betaxolol, and the        like, or pharmaceutically acceptable salts or prodrugs thereof;    -   Adrenergic Agonists including    -   non-selective adrenergic agonists such as epinephrine borate,        epinephrine hydrochloride, and dipivefrin, and the like, or        pharmaceutically acceptable salts or prodrugs thereof; and    -   α₂-selective adrenergic agonists such as apraclonidine,        brimonidine, and the like, or pharmaceutically acceptable salts        or prodrugs thereof;    -   Carbonic Anhydrase Inhibitors including acetazolamide,        dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and        the like, or pharmaceutically acceptable salts or prodrugs        thereof;    -   Cholinergic Agonists including    -   direct acting cholinergic agonists such as charbachol,        pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine, and        the like, or pharmaceutically acceptable salts or prodrugs        thereof;    -   chlolinesterase inhibitors such as demecarium, echothiophate,        physostigmine, and the like, or pharmaceutically acceptable        salts or prodrugs thereof;    -   Glutamate Antagonists such as memantine, amantadine,        rimantadine, nitroglycerin, dextrophan, detromethorphan,        CGS-19755, dihydropyridines, verapamil, emopamil,        benzothiazepines, bepridil, diphenylbutylpiperidines,        diphenylpiperazines, HOE 166 and related drugs, fluspirilene,        eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S,        flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine,        verapamil, lidoflazine, prenylamine lactate, amiloride, and the        like, or pharmaceutically acceptable salts or prodrugs thereof;    -   Prostamides such as bimatoprost, or pharmaceutically acceptable        salts or prodrugs thereof; and    -   Prostaglandins including travoprost, UFO-21, chloprostenol,        fluprostenol, 13,14-dihydro-chloprostenol, latanoprost and the        like.

EXAMPLES

Various aspects of the present invention are illustrated by thefollowing non-limiting examples. The examples are for illustrativepurposes and are not a limitation on any practice of the presentinvention. It will be understood that variations and modifications canbe made without departing from the spirit and scope of the invention.One of ordinary skill in the art readily knows how to synthesize orcommercially obtain the reagents and components described herein.

X-Ray powder diffraction patterns (XRPD) were obtained for thecrystalline form described herein under the following conditions:

-   -   Equipment: Rigaku Smart-Lab    -   Scan range: 2 to 40° (2θ)    -   Scan speed: 3° (2θ) per minute    -   Step width: 0.02° (2θ)    -   X-ray information: Cu Kα, λ=1.54 Å, 40 kV/44 mA

Approximately 5-10 mg of the sample was gently applied on a lowbackground Si holder and subjected to XRPD scanning.

Differential scanning calorimetry was performed by loading 2 to 6 mgmaterial in a standard, crimped, aluminum DSC sample pan and thensubjecting the sample to a heat ramp from 20 to 350° C. at a rate of 10°C. per min.

The compound 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide described hereincan by synthesized according to the procedures in U.S. Pat. No.6,602,900.

Example 1

The compound 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide is dissolved ina suitable solvent such as acetonitrile, dichloromethane, ethanol, ethylacetate, 2-methyltetrahydrofuran, 1-propanol, or a mixture of tolueneand methanol (v/v 25/1). Evaporation of the solvent therefrom followedby trituration of the resulting oil with diethyl ether providedcrystalline Form A, as determined by XRPD. Alternatively, trituration ofthe resulting oil with acetonitrile provided crystalline Form B, asdetermined by XRPD.

Example 2

A warm solution of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamidewas prepared in a variety of solvents, then allowed to slowly cool untilcrystals were observed. The combination of solvents/cooling conditionswhich facilitated formation of crystalline Form A is summarized in Table1:

TABLE 1 Solvent Conditions Acetonitrile 95° C. → room temperatureAcetonitrile (dry) 80° C. → room temperature Ethyl acetate 90° C. → roomtemperature Ethyl acetate (dry) 80° C. → room temperature Acetone/hexane(v/v 1/1.4) 75° C. → room temperature 2-propanol/diethyl ether (v/v 1/5)Room temperature → −20° C. Methyl ethyl ketone/hexane (v/v 7/10; dry)80° C. → room temperature

The combination of solvents/cooling conditions which facilitatedformation of crystalline Form B is summarized in Table 2:

TABLE 2 Solvent Conditions Dioxane/methyl tert-butyl ether (v/v 1/4)Room temperature → −20° C. 2-methyltetrahydrofuran/hexane (v/v 3/2) Roomtemperature → 5° C. 2-methyltetrahydrofuran/hexane (v/v 7/5) 70° C. →room temperature

As shown in Tables 1 and 2, the crystalline form of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide can becontrolled by the choice of solvent from which the compound isprecipitated, and the temperatures employed to induce crystallization.

Example 3

A slurry of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamidewas prepared in a variety of media, then allowed to stand at roomtemperature for a time sufficient to allow crystals to form. Thediluents which facilitated formation of crystalline Form A aresummarized in Table 3:

TABLE 3 Crystallization Diluent time, days Acetone (dry) 3 Acetonitrile(dry) 3 Diethyl ether 4 Ethyl acetate 5 1-butanol/methyl tert-butylether (v/v 1/20; dry) 3 Dioxane/methyl tert-butyl ether (v/v 1/4; dry) 3Ethanol/toluene (v/v 1/40; dry) 3 Methanol/diethyl ether (v/v1/10) 12Methanol/diethyl ether (v/v1/20) 5 Methyl ethyl ketone/heptane (v/v 1/1;dry) 3 2-methyltetrahydrofuran/hexane (v/v1/1) 72-methyltetrahydrofuran/hexane (v/v1/1; dry) 3 Tetrahydrofuran/hexane(v/v1/1; dry) 3 Toluene (dry) 3

The diluents which facilitated formation of crystalline Form B aresummarized in Table 4:

TABLE 4 Crystallization Diluent time, days Diethyl ether (wet) 4 Methylethyl ketone 5 1-butanol/methyl tert-butyl ether (v/v 1/20) 41-butanol/methyl tert-butyl ether (v/v 1/20; wet) 6 Dioxane/methyltert-butyl ether (v/v 1/4) 7 Ethanol/toluene (v/v 1/40) 7 Methyl ethylketone (v/v 1/1) 5 Tetrahydrofuran/hexane (v/v 1/2) 4 Toluene 5

As shown in Tables 3 and 4, the crystalline form of the compound7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide can becontrolled by the choice of diluent from which the compound iscrystallized using slurry crystallization methods.

Example 4

The compound 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide can also becrystallized employing vapor diffusion techniques. Crystalline Form Acan be obtained when said compound is dissolved in a polar solvent suchas acetonitrile, and then exposed to a non-polar solvent such as tolueneat room temperature.

Alternatively, crystalline Form B can be obtained when said compound isdissolved in a polar solvent such as acetone, and then exposed to anon-aromatic, non-polar solvent such as hexane at room temperature.

Example 5

The compound 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide can be preparedin substantially amorphous form by exposing said compound to atemperature of at least about 40° C. for at least 12 hours.

Example 6

A sample of 5-10 milligrams of crystalline Form A was maintained at atemperature of 22±2° C. and relative humidity of 0% for 144 hours Whenthe XRPD spectrum of the sample after being maintained at 22±2° C. andrelative humidity of 0% for 144 hours (see FIG. 4A) was compared to theXRPD spectrum of the sample before being maintained under thoseconditions, no significant change was observed in the XRPD spectrum inthat the peaks at about 12.01, 14.09, 20.14, 20.47 and 23.72 degrees 2θwere still present, indicating that crystal Form A had remainedsubstantially unchanged. A similar lack of significant change in theXRPD pattern was also observed when a sample was stored at 40° C. for 25minutes (see FIG. 4B).

In addition, another sample of 5-10 milligrams of crystalline Form A wasmaintained at a temperature of 22±2° C. and relative humidity of 59% for144 hours. When the XRPD spectrum of the sample after being maintainedat 22±2° C. and relative humidity of 59% for 144 hours (see FIG. 5) wascompared to the XRPD spectrum of the sample before being maintainedunder those conditions, the XRPD spectrum revealed the presence of peaksat about 11.64, 19.57, 21.99, 22.74 and 25.06 degrees 2θ, indicatingthat a substantial portion of crystalline Form A had converted tocrystalline Form B.

Example 7

A sample of 5-10 milligrams of crystalline Form B was maintained at atemperature of 22±2° C. and relative humidity of 59% for 120 hours. Whenthe XRPD spectrum of the sample after being maintained at 22±2° C. andrelative humidity of 59% for 120 hours (see FIG. 6A) was compared to theXRPD spectrum of the sample before being maintained under thoseconditions, no significant change was observed in the XRPD spectrum inthat the peaks at about 11.64, 19.57, 21.99, 22.74 and 25.06 degrees 2θwere still present, indicating that crystal Form B had remainedsubstantially unchanged. A similar lack of significant change in theXRPD pattern was also observed when a sample was stored at 40° C. for 25minutes (see FIG. 6B).

In addition, another sample of 10-50 grams of crystalline Form B wasmaintained at a temperature of 22±2° C. and relative humidity of 0% for120 hours. When the XRPD spectrum of the sample after being maintainedat 22±2° C. and relative humidity of 0% for 120 hours (see FIG. 7) wascompared to the XRPD spectrum of the sample before being maintainedunder those conditions, the XRPD spectrum revealed the sample to be apoorly-crystalline mixture of Forms A and B.

In addition, a similar sample of crystalline Form B was maintained at atemperature of 40° C. for 16 hours. When the XRPD spectrum of the sampleafter being maintained 40° C. for 16 hours (see FIG. 8) was compared tothe XRPD spectrum of the sample before being maintained under thoseconditions, the XRPD spectrum revealed the disappearance of peaks atabout 11.64, 19.57, 21.99, 22.74 and 25.06 degrees 2θ, indicating that asubstantial portion of crystalline Form B had converted to the amorphousform.

Various modifications of the present invention, in addition to thoseshown and described herein, will be apparent to those skilled in the artof the above description. Such modifications are also intended to fallwithin the scope of the appended claims.

Patents and publications mentioned in the specification are indicativeof the levels of those skilled in the art to which the inventionpertains. These patents and publications are incorporated herein byreference to the same extent as if each individual application orpublication was specifically and individually incorporated herein byreference.

The foregoing description is illustrative of particular embodiments ofthe invention, but is not meant to be a limitation upon the practicethereof. The following claims, including all equivalents thereof, areintended to define the scope of the invention.

What is claimed is:
 1. A pharmaceutical composition comprising atherapeutically effective amount of a crystalline form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide:

in an ophthalmically acceptable carrier, wherein the crystalline form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamidehas an X-ray powder diffraction pattern with peaks at 12.0±0.1,14.1±0.1, 20.1±0.1, 20.5±0.1 and 23.7±0.1 degrees 2θ.
 2. Apharmaceutical composition comprising a therapeutically effective amountof a crystalline form of 7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide:

in an ophthalmically acceptable carrier, wherein the crystalline form of7-[3α,5α-dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dichloro)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamidehas an X-ray powder diffraction pattern with peaks at 11.6±0.1,19.6±0.1, 22.0±0.1, 22.7±0.1 and 25.1±0.1 degrees 2θ.
 3. A method fortreating ocular hypertension or glaucoma comprising administering to asubject in need thereof a composition according to claim
 1. 4. A methodfor treating ocular hypertension or glaucoma comprising administering toa subject in need thereof a composition according to claim 2.